Trial Evaluating the Safety of 2 Schedules of Cabazitaxel in Elderly Men With mCRPC Previously Treated With a Docetaxel (CABASTY)

Trial Evaluating the Safety of 2 Schedules of Cabazitaxel in Elderly Men With mCRPC Previously Treated With a Docetaxel

Randomized Multicenter, Phase III Trial Evaluating the Safety of 2 Schedules of Cabazitaxel (Bi-weekly Versus Tri-weekly) Plus Prednisone in Elderly Men (≥ 65years) With mCRPC Previously Treated With a Docetaxel-containing Regimen

The purpose of this study is to evaluate the incidence of grade ≥ 3 neutropenia and/or neutropenic complications (febrile neutropenia, neutropenic infection) with two schedules of cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men (≥ 65 years) with mCRPC previously treated with a docetaxel-containing regimen.

Randomized, open-label, phase 3 trial in mCRPC patients aged ≥ 65 years. Number of subjects: Total:170 to 200 (85 to 100 per arm) Treatment: Arm A : cabazitaxel 25 mg/m² on Day 1 of a 3-week cycle plus daily prednisone or Arm B: cabazitaxel 16 mg/m² on Day 1 and Day 15 of a 4-week cycle plus daily prednisone. Treatment will be continued for a maximum of 10 cycles unless there is documented disease progression or unacceptable toxicity. Standard cabazitaxel premedication will be used Prophylactic G-CSF (GRANOCYTE) will be injected from Day 3 to Day 7 after every administration cycle of cabazitaxel· All new hormonal treatment, including ODM-201, prior to study entry is allowed. Patients who received Radium-223 are eligible for this study Treatment with LHRH should not be discontinued. Exploratory assessments: CT-Scan (abdominal/pelvic/chest) or whole body MRI and Bone scan: at screening, every 3 months and EOT. FACT-P questionnaire:at C1D1,each subsequent visit and EOT Exploratory substudy Blood samples will be collected in France (4 or 6 sites) and the Netherlands (2 sites). Biomarker analysis will be conducted at the Urology and The Tumor Immunology Laboratory at Radboud UMC in NL. Biomarker schedule Arm A (25mg/m2): Baseline - Week 6 - Week 12 - at progression Arm B (16mg/m2): Baseline - Week 6 - Week 12 - at progression Optional sample points are at C1D8. Number of subjects: 50 Statistical analysis: A sample size of 77 to 90 evaluable patients per arm will achieve 80% power to detect a 20% difference in G3 neutropenia incidence between the 2 arms. The incidence in group cabazitaxel 25 mg/m2 q3w is assumed to be 32% and 12% on bi-weekly cabazitaxel arm. The test used is a two-sided Fisher's exact test at 0.05 significance level. Assuming 10% non-evaluable patients, 85 to 100 patients should be included in each arm for a total of 170 to 200. Patients will be stratified according to G8 score (< 14 vs. ≥ 14), and age (< 70 vs. ≥ 70) before randomization. Exploratory sub-study The trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 nThe trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 neutropenia incidence between arms (32% in arm A vs 12% arm B; power 80% with two-sided alpha of 5%, correcting for 10% non-evaluable patients (=17 patients). From the 153 to 180 evaluable patients, we have 76 to 90 patients in each arm, of which we expect 40-60 evaluable patients for translational studies (calculations performed on 25 per arm). In arm A, we expect 8 patients (32% of patients) with G3 neutropenia, and 17 patients that do not. In arm B, we expect 3 patients (12% of patients) with G3 neutropenia, and 22 patients that do not. For the MDSC analyses, we therefore will be comparing 11 patients with G3 neutropenia to 39 patients. For all continuous variables, including all immune subpopulations present in blood, mean (sd) will be presented if the distribution seems to be symmetric and in case of a skewed distribution the median and IQR. For categorical data, number and percentage will be presented. For comparison of continuous data linear regression analyses or correlation (Spearman or Pearson) will used. For comparison of continuous data with categorical data logistic regression analysis will be used. For comparison of two sets of categorical data the chi-square test of Fisher's exact test will be utilized. For the radiological PFS analyses the estimates of the hazard ratio and corresponding 95% confidence interval will be tested using a Cox Proportional hazard model. For the overall survival, a stratified log-rank test will be used to compare between groups.

Cabazitaxel 25 mg/m² intravenously over 1 hour on Day 1of a 3-week cycle, plus prednisone (or prednisolone) 10 mg orally given daily for a maximum of 10 cycles (ie 30 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel.

Cabazitaxel 16 mg/m2 on Day 1 and Day 15 of a 4-week cycle plus prednisone (or prednisolone) 10 mg per day up to 10 cycles (ie 40 weeks of treatment). Prophylactic Granulocyte colony-stimulating factor G-CSF (Granocyte) will be injected from Day 3 to Day 7 after every administration of cabazitaxel.

Arm A : cabazitaxel 25 mg/m² on Day 1 of a 3-week cycle plus daily prednisone or Arm B: cabazitaxel 16 mg/m² on Day 1 and Day 15 of a 4-week cycle plus daily prednisone. Treatment will be continued for a maximum of 10 cycles unless there is documented disease progression or unacceptable toxicity. Standard cabazitaxel premedication will be used

Arm A:plus prednisone 10 mg orally given daily for a maximum of 10 cycles Arm B: plus prednisone 10 mg orally given per day up to 10 cycles

Primary prophylaxis with Granulocyte Colony-Stimulating Factor (G-CSF) will be injected from Day 3 to Day 7 after every administration of cabazitaxel

To evaluate the incidence of grade ≥ 3 neutropenia (measured at Day 7 and Day 14) and/or neutropenic complications (febrile neutropenia, neutropenic infection) with two schedules of cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men (≥ 65 years) with mCRPC previously treated with a docetaxel-containing regimen. with two schedules of -+cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men with mCRPC previously treated with a docetaxel-containing regimen

Factors influencing survival (duration of response to first ADT, serum testosterone, cumulative dose of cabazitaxel, neutrophils/lymphocytes ratio, Gleason score, G8, grade ≥3 neutropenia)

Proportion of patients achieving a best objective response of SD, PR or CR according to RECIST 1.1 specifically comparing those achieving >30% and >50% decrease in MDSC post-induction compared to those who did not achieve this reduction.

Proportion of patients achieving a >50% PSA response at 12 weeks and at any time specifically comparing those achieving >30% and >50% decrease in MDSC post-induction compared to those who did not achieve this reduction.

Radiological progression-free survival (rPFS) according to PCWG2 criteria for all patients, in relation to percentage MDSC change (% maximum change and those achieving >30% and >50% decrease)

Differences in peripheral blood immune populations (MDSCs, regulatory T-cells, T-effector and natural killer [NK] cells) with cabazitaxel responsiveness for Q2W and Q3W dosing schedule at week 6 and week 12

biomarkers analysis collection of blood (EDTA tube) at Baseline, C1D8,week 6, week 12 and EOT Collection of blood (RNA Paxgene): baseline platelet poor plasma isolation, PBMC isolation, PMN isolation and Flow cytometry assessments and FACS sorting Next-generation targeted sequencing of cfDNA RNA sequencing of baseline PaxGene

Hematology every week until EOT collection of blood (EDTA tube) at Baseline, C1D8,week 6, week 12 and EOT Collection of blood (RNA Paxgene): baseline platelet poor plasma isolation, PBMC isolation, PMN isolation and Flow cytometry assessments and FACS sorting Next-generation targeted sequencing of cfDNA RNA sequencing of baseline PaxGene

Associations between cabazitaxel dose, presence of neutropenia (C1D8), NLR conversion (wk6 and wk12) and MDSC decline (wk6 and wk12)

biomarkers analysis collection of blood (EDTA tube) at Baseline, C1D8,week 6, week 12 and EOT Collection of blood (RNA Paxgene): baseline platelet poor plasma isolation, PBMC isolation, PMN isolation and Flow cytometry assessments and FACS sorting Next-generation targeted sequencing of cfDNA RNA sequencing of baseline PaxGene

To evaluate changes in peripheral blood immune populations at failure on cabazitaxel, with particular focus on CD38-positive MDSC subsets

biomarkers analysis collection of blood (EDTA tube) at Baseline, C1D8,week 6, week 12 and EOT Collection of blood (RNA Paxgene): baseline platelet poor plasma isolation, PBMC isolation, PMN isolation and Flow cytometry assessments and FACS sorting Next-generation targeted sequencing of cfDNA RNA sequencing of baseline PaxGene

Associations between baseline MDSC and molecular underpinning (from cfDNA, specifically studying MYCN amplification and PTEN / TP53 aberration)

biomarkers analysis collection of blood (EDTA tube) at Baseline, C1D8,week 6, week 12 and EOT Collection of blood (RNA Paxgene): baseline platelet poor plasma isolation, PBMC isolation, PMN isolation and Flow cytometry assessments and FACS sorting Next-generation targeted sequencing of cfDNA RNA sequencing of baseline PaxGene

Inclusion Criteria: Patient aged ≥ 65 years with mCRPC previously treated with docetaxel Medical or surgical castration with castrate level of testosterone (< 50 ng/dl) based on the EAU definition of castrate level of testosterone Progressive disease according to PCWG2 Histologically proven prostate carcinoma Health status allowing use of chemotherapy: G8 > 14; or G8 score ≤ 14 with geriatric assessment concluding to reversible impairment allowing use of chemotherapy ECOG-PS 0, 1 or 2(ECOG-PS 2 should be related to prostate cancer) Adequate hematologic, liver and renal functions: Neutrophil count ≥1.5 109/L Haemoglobin ≥10 g/ dL Platelet count ≥100.109/L Total bilirubin ≤ 1 the upper limit of normal (ULN) Transaminases ≤ 1.5 ULN Serum creatinine ≤ 2.0 ULN Ongoing LHRH therapy at study entry Signed informed consent Exclusion Criteria: History of severe hypersensitivity reaction (≥grade 3) to docetaxel History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus) Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Appendix E) PS >2 not related to prostate cancer disease G8 ≤ 14 with geriatric assessment contra-indicating standard cabazitaxel regimen Concomitant vaccination with yellow fever vaccine Patient who cannot be regularly followed or cannot answer to quality of life questionnaires because of psychological, social, familial or geographic reasons Participation in another clinical trial with any investigational drug within 30 days prior to study enrolment.

Pobel C, Auclin E, Procureur A, Clement-Zhao A, Simonaggio A, Delanoy N, Vano YA, Thibault C, Oudard S. Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review. Future Oncol. 2021 Jan;17(1):91-102. doi: 10.2217/fon-2020-0672. Epub 2020 Dec 2.